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1.  EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update 
Annals of the Rheumatic Diseases  2013;73(3):492-509.
In this article, the 2010 European League against Rheumatism (EULAR) recommendations for the management of rheumatoid arthritis (RA) with synthetic and biological disease-modifying antirheumatic drugs (sDMARDs and bDMARDs, respectively) have been updated. The 2013 update has been developed by an international task force, which based its decisions mostly on evidence from three systematic literature reviews (one each on sDMARDs, including glucocorticoids, bDMARDs and safety aspects of DMARD therapy); treatment strategies were also covered by the searches. The evidence presented was discussed and summarised by the experts in the course of a consensus finding and voting process. Levels of evidence and grades of recommendations were derived and levels of agreement (strengths of recommendations) were determined. Fourteen recommendations were developed (instead of 15 in 2010). Some of the 2010 recommendations were deleted, and others were amended or split. The recommendations cover general aspects, such as attainment of remission or low disease activity using a treat-to-target approach, and the need for shared decision-making between rheumatologists and patients. The more specific items relate to starting DMARD therapy using a conventional sDMARD (csDMARD) strategy in combination with glucocorticoids, followed by the addition of a bDMARD or another csDMARD strategy (after stratification by presence or absence of adverse risk factors) if the treatment target is not reached within 6 months (or improvement not seen at 3 months). Tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, biosimilars), abatacept, tocilizumab and, under certain circumstances, rituximab are essentially considered to have similar efficacy and safety. If the first bDMARD strategy fails, any other bDMARD may be used. The recommendations also address tofacitinib as a targeted sDMARD (tsDMARD), which is recommended, where licensed, after use of at least one bDMARD. Biosimilars are also addressed. These recommendations are intended to inform rheumatologists, patients, national rheumatology societies and other stakeholders about EULAR's most recent consensus on the management of RA with sDMARDs, glucocorticoids and bDMARDs. They are based on evidence and expert opinion and intended to improve outcome in patients with RA.
doi:10.1136/annrheumdis-2013-204573
PMCID: PMC3933074  PMID: 24161836
Rheumatoid Arthritis; DMARDs (synthetic); DMARDs (biologic); Treatment; Early Rheumatoid Arthritis
2.  Safety with Ocrelizumab in Rheumatoid Arthritis: Results from the Ocrelizumab Phase III Program 
PLoS ONE  2014;9(2):e87379.
Objective
The objective was to determine the safety of ocrelizumab (OCR) in patients with rheumatoid arthritis (RA).
Methods
This was an analysis of the double-blind, placebo-controlled periods and long-term follow-up of 4 OCR phase III trials in RA (SCRIPT, STAGE, FILM and FEATURE). Safety data per study and the results of a meta-analysis of serious infectious events (SIEs) are presented.
Results
Overall, 868 patients received placebo, 1064 patients OCR 200 mg×2 (or 400 mg×1) (OCR200), and 827 patients OCR 500 mg×2 (OCR500) plus background methotrexate (MTX) at baseline and 24 weeks. During the double-blind, placebo-controlled periods, the incidence of adverse events and serious adverse events was comparable between the OCR+MTX and placebo +MTX groups. Infusion-related reactions were more common with OCR+MTX and decreased in frequency with subsequent infusions. Serious infusion-related reactions were rare (0.1%). Serious infections occurred more frequently with OCR500+MTX. In the meta-analysis, a statistically significant difference from placebo +MTX in incidence of SIEs per 100 patient-years of 2.4 (95% CI, 0.3–4.5) was observed with OCR500+MTX, but not with OCR200+MTX (0.6; 95% CI, −1.3 to 2.4). Patients recruited in Asia exhibited a higher risk of serious infections (hazard ratio, 1.78; 95% CI, 1.03–3.06). The incidence of human anti-human antibodies was <5%. Long-term follow-up indicated no differences in malignancy rates between the treatment groups. There was no apparent difference in time to B-cell repletion between the OCR dose groups.
Conclusions
In placebo-controlled clinical trials of RA, OCR500+MTX was associated with a higher risk of serious infections compared with placebo +MTX. The safety profile of OCR 200+MTX was comparable with placebo+MTX.
Trial Registration
STAGE Clinical Trials.gov NCT00406419
SCRIPT Clinical Trials.gov NCT00476996
FILM Clinical Trials.gov NCT00485589
FEATURE Clinical Trials.gov NCT00673920
doi:10.1371/journal.pone.0087379
PMCID: PMC3911947  PMID: 24498318
3.  The TRACTISS Protocol: a randomised double blind placebo controlled clinical TRial of Anti-B-Cell Therapy In patients with primary Sjögren’s Syndrome 
Background
Primary Sjögren’s Syndrome (PSS) mainly affects women (9:1 female:male ratio) and is one of the commonest autoimmune diseases with a prevalence of 0.1 – 0.6% of adult women. For patients with PSS there is currently no effective therapy that can alter the progression of the disease. The aim of the TRACTISS study is to establish whether in patients with PSS, treatment with rituximab improves clinical outcomes.
Methods/design
TRACTISS is a UK multi-centre, double-blind, randomised, controlled, parallel group trial of 110 patients with PSS. Patients will be randomised on a 1:1 basis to receive two courses of either rituximab or placebo infusion in addition to standard therapy, and will be followed up for up to 48 weeks. The primary objective is to assess the extent to which rituximab improves symptoms of fatigue and oral dryness. Secondary outcomes include ocular dryness, salivary flow rates, lacrimal flow, patient quality of life, measures of disease damage and disease activity, serological and peripheral blood biomarkers, and glandular histology and composition.
Discussion
The TRACTISS trial will provide direct evidence as to whether rituximab in patients with PSS leads to an improvement in patient symptoms and a reduction in disease damage and activity.
Trial registration
UKCRN Portfolio ID: 9809 ISRCTN65360827.
doi:10.1186/1471-2474-15-21
PMCID: PMC3937118  PMID: 24438039
Sjögren’s syndrome; Rituximab; Anti-B-cell; Double-blind; Placebo; Trial
4.  Validity, Reliability, and Feasibility of Durometer Measurements of Scleroderma Skin Disease in a Multicenter Treatment Trial 
Arthritis and rheumatism  2008;59(5):10.1002/art.23564.
Objective
To determine the validity, reliability, and feasibility of durometer measurements of skin hardness as an outcome measure in clinical trials of scleroderma.
Methods
Skin hardness was measured during a multicenter treatment trial for scleroderma using handheld digital durometers with a continuous scale. Skin thickness was measured by modified Rodnan skin score (MRSS). Other outcome data collected included the Scleroderma Health Assessment Questionnaire. In a reliability exercise in advance of the trial, 9 investigators examined the same 5 scleroderma patients by MRSS and durometry.
Results
Forty-three patients with early diffuse cutaneous systemic sclerosis were studied at 11 international centers (mean age 49 years [range 24–76], median disease duration 6.4 months [range 0.3–23], and median baseline MRSS 22 [range 11–38]). The reliability of durometer measurements was excellent, with high interobserver intraclass correlation coefficients (ICCs) (0.82–0.92), and each result was greater than the corresponding skin site ICCs for MRSS (0.54–0.85). Baseline durometer scores correlated well with MRSS (r = 0.69, P < 0.0001), patient self-assessments of skin disease (r = 0.69, P < 0.0001), and Health Assessment Questionnaire (HAQ) disability scores (r = 0.34, P = 0.03). Change in durometer scores correlated with change in MRSS (r = 0.70, P < 0.0001), change in patient self-assessments of skin disease (r = 0.52, P = 0.003), and change in HAQ disability scores (r = 0.42, P = 0.017). The effect size was greater for durometry than for MRSS or patient self-assessment.
Conclusion
Durometer measurements of skin hardness in patients with scleroderma are reliable, simple, accurate, demonstrate good sensitivity to change compared with traditional skin scoring, and reflect patients' self-assessments of their disease. Durometer measurements are valid, objective, and scalable, and should be considered for use as a complementary outcome measure to skin scoring in clinical trials of scleroderma.
doi:10.1002/art.23564
PMCID: PMC3887555  PMID: 18438905
5.  LDL Cholesterolemia as a Novel Risk Factor for Radiographic Progression of Rheumatoid Arthritis: A Single-Center Prospective Study 
PLoS ONE  2013;8(7):e68975.
Dyslipidemia has been implicated in various musculoskeletal diseases, including rheumatoid arthritis (RA). Evidence is emerging that there might be a pathogenic interaction among inflammation, dyslipidemia, and adipokines. We prospectively investigated the association of cumulative lipid levels with radiographic progression of RA. RA patients (n = 242) underwent plasma cholesterol assessment at four visits. Disease activity parameters and X-rays of the hands and feet were also serially monitored in these patients. The cumulative inflammatory burden and lipid levels were estimated by time-integrated values. Serum leptin and adiponectin concentrations were determined by ELISA. When patients were divided into three groups according to time-integrated lipid levels, as expected, patients with LDL cholesterol and/or triglyceride levels in the third tertile had persistently higher ESR and CRP levels. In parallel, a more rapid radiographic progression over two years was observed in patients with higher LDL cholesterol and/or triglyceride levels. In multivariate analysis, time-integrated LDL cholesterol was independently associated with radiographic progression. Particularly, the risk of radiographic progression was 5.6-fold in a subgroup with both LDL cholesterol and triglyceride levels in the third tertile. Moreover, LDL cholesterol synergistically increased the adjusted probability of radiographic progression in patients with high serum leptin levels but not in those without. These results demonstrate that LDL cholesterolemia is a novel serum marker that can be used to predict radiographic progression of RA, which seems to be related to circulatory leptin levels. We suggest that personalized and more aggressive anti-rheumatic therapy is required for dyslipidemic subgroups in RA patients.
doi:10.1371/journal.pone.0068975
PMCID: PMC3726747  PMID: 23922673
6.  Value of Ultrasound in Rheumatologic Diseases 
Journal of Korean Medical Science  2013;28(4):497-507.
The use of musculoskeletal ultrasound in rheumatology clinical practice has rapidly increased over the past decade. Ultrasound has enabled rheumatologists to diagnose, prognosticate and monitor disease outcome. Although international standardization remains a concern still, the use of ultrasound in rheumatology is expected to grow further as costs fall and the opportunity to train in the technique improves. We present a review of value of ultrasound, focusing on major applications of ultrasound in rheumatologic diseases.
doi:10.3346/jkms.2013.28.4.497
PMCID: PMC3617300  PMID: 23580002
Rheumatology Ultrasound; Musculoskeletal Ultrasound; Doppler; Arthritis
7.  The TICOPA protocol (TIght COntrol of Psoriatic Arthritis): a randomised controlled trial to compare intensive management versus standard care in early psoriatic arthritis 
Background
Psoriatic Arthritis (PsA) is estimated to occur in 10-15% of people with psoriasis and accounts for 13% of people attending early arthritis clinics. With an increasing awareness of the poor outcomes associated with PsA and the availability of new effective, but costly, treatments, there is an urgent need to research the optimal treatment for patients with PsA. The aim of the TICOPA study is to establish whether, in treatment naive early PsA patients, “tight control” intensive management with protocol driven therapies and pre-defined objective targets for treatment can improve clinical outcome compared to standard care alone.
Methods/design
TICOPA is a UK multicentre, open-label, randomised controlled, parallel group trial of 206 patients with early PsA. Patients will be randomised on a 1:1 basis to receive either standard care (12 weekly review) or intensive management (4 weekly review) for a period of 48 weeks. Patients assigned to the intensive management group will follow a strict treatment protocol whereby dose continuation/escalation is determined through the objective assessment of the minimal disease activity (MDA) criteria. Patients assigned to the standard care group will have treatment prescribed as felt appropriate by the treating clinician, with no set protocol. The primary objective of the trial is to compare intensive management with standard care in terms of the proportion of patients achieving an ACR 20 response at 48 weeks post-randomisation, in order to determine whether intensive management has superior clinical efficacy. Key secondary outcomes include ACR 50 and 70, PASI 75 and X-ray Van der Heijde score at 48 weeks post-randomisation along with cost-effectiveness at 12, 24 and 28 weeks.
Discussion
The TICOPA trial will provide direct evidence as to whether the use of early and intensive treatment in PsA in routine clinical care leads to an improvement in patients’ disease activity and a reduction in radiological joint damage.
Trial registration
ISRCTN30147736, NCT01106079
doi:10.1186/1471-2474-14-101
PMCID: PMC3610193  PMID: 23517506
Psoriatic arthritis; Early psoriatic arthritis; Tight management; Tight control; Intensive management; Standard care
8.  The evolution of ultrasound in rheumatology 
Musculoskeletal ultrasound is a powerful tool not only for evaluating joint and related structures but also for assessing disease activity. Ultrasound in rheumatology has rapidly evolved and been incorporated into routine clinical practice over the past decade. Moreover, technological development of equipment has made it more accessible for rheumatologists. We present a review of advances in ultrasound in rheumatology, focusing on major chronological developments.
doi:10.1177/1759720X12460116
PMCID: PMC3512173  PMID: 23227117
evolution; musculoskeletal ultrasound; rheumatology ultrasonography
9.  Improvements in health-related quality of life after treatment with tocilizumab in patients with rheumatoid arthritis refractory to tumour necrosis factor inhibitors: results from the 24-week randomized controlled RADIATE study 
Rheumatology (Oxford, England)  2012;51(10):1860-1869.
Objective. To investigate the effect of tocilizumab on patient-reported outcomes (PROs) in RA patients with inadequate responses to TNF inhibitors (TNFis).
Methods. In a Phase III randomized controlled trial, 489 patients received 4 or 8 mg/kg tocilizumab or placebo every 4 weeks plus MTX for 24 weeks. Mean changes from baseline over time and proportions of patients reporting improvements greater than or equal to minimum clinically important differences (MCIDs) in PROs were analyzed.
Results. At week 24, 8 mg/kg resulted in significantly greater improvements vs placebo in pain, global assessment of disease activity (P = 0.001), Health Assessment Questionnaire-Disability Index (HAQ-DI; P < 0.0001), Functional Assessment of Chronic Illness Therapy-Fatigue (P = 0.0150) and Medical Outcomes Survey Short Form 36 (SF-36 v2) Physical Component Summary (PCS; P = 0.0003) scores, all greater than MCID; 4 mg/kg resulted in greater improvements in pain (P = 0.0100), HAQ-DI (P = 0.0030) and SF-36 PCS (P = 0.0020) scores. Tocilizumab-associated improvements were evident as early as week 2. At week 24, more tocilizumab-treated than control patients reported improvements greater than or equal to MCID in SF-36 domain scores and related PROs (50.9–84.9% vs 35.0–51.7%) and achieved ACR50 responses and/or Disease Activity Score 28 (DAS28) remission with PRO improvements greater than or equal to MCID (36.2–51.2% vs 10–20.7% and 10.7–37.5% vs 0.0–3.4%, respectively).
Conclusion. Tocilizumab treatment in patients with inadequate responses to TNFis resulted in rapid and sustained improvements in multiple PROs that were statistically significant and clinically meaningful, consistent with previous efficacy reports.
Trial Registration. ClinicalTrials.gov, http://clinicaltrials.gov/, NCT00106522.
doi:10.1093/rheumatology/kes131
PMCID: PMC3448882  PMID: 22753773
rheumatoid arthritis; tocilizumab; health-related quality of life; patient-reported outcomes; randomized controlled trial
10.  American College of Rheumatology/European League against Rheumatism Preliminary Definition of Remission in Rheumatoid Arthritis for Clinical Trials 
Arthritis and rheumatism  2011;63(3):573-586.
Background
With remission in rheumatoid arthritis (RA) an increasingly attainable goal, there is no widely used definition of remission that is stringent but achievable and could be applied uniformly as an outcome in clinical trials.
Methods
A committee consisting of members of the American College of Rheumatology, the European League Against Rheumatism and the Outcome Measures in Rheumatology Initiative (OMERACT) met to guide the process and review prespecified analyses from clinical trials of patients with RA. The committee requested a stringent definition (little, if any, active disease) and decided to use core set measures to define remission including at least joint counts and an acute phase reactant. Members were surveyed to select the level of each core set measure consistent with remission. Candidate definitions of remission were tested including those that constituted a number of individual measures in remission (Boolean approach) as well as definitions using disease activity indexes. To select a definition of remission, trial data were analyzed to examine the added contribution of patient reported outcomes and the ability of candidate measures to predict later good x-ray and functional outcomes.
Results
Survey results for the definition of remission pointed to indexes at published thresholds and to a count of core set measures with each measure scored as 1 or less (e.g. tender and swollen joint counts, CRP and global assessments on 0-10 scale). Analyses suggested the need to include a patient reported measure. Examination of 2 year follow-up data suggested that many candidate definitions performed comparably in terms of predicting later good x-ray and functional outcomes, although DAS28 based measures of remission did not predict good radiographic outcomes as well as did the other candidate definitions. Given these and other considerations, we propose that a patient be defined as in remission based on one of two definitions : 1: When their scores on the following measures are all <1: tender joint count, swollen joint count, CRP (in mg/dL) and patient global assessment (0-10 scale), OR 2: when their score on the SDAI is < 3.3.
Conclusion
We propose two new definitions of remission both of which can be uniformly applied and widely used in RA clinical trials. We recommend that one of these be selected in each trial as an outcome and that the results on both be reported in each trial.
doi:10.1002/art.30129
PMCID: PMC3115717  PMID: 21294106
11.  Pressure and pain In Systemic sclerosis/Scleroderma - an evaluation of a simple intervention (PISCES): randomised controlled trial protocol 
Background
Foot problems associated with Systemic Sclerosis (SSc)/Scleroderma have been reported to be both common and disabling. There are only limited data describing specifically, the mechanical changes occurring in the foot in SSc. A pilot project conducted in preparation for this trial confirmed the previous reports of foot related impairment and reduced foot function in people with SSc and demonstrated a link to mechanical etiologies. To-date there have been no formal studies of interventions directed at the foot problems experienced by people with Systemic Sclerosis. The primary aim of this trial is to evaluate whether foot pain and foot-related health status in people with Systemic Sclerosis can be improved through the provision of a simple pressure-relieving insole.
Methods
The proposed trial is a pragmatic, multicenter, randomised controlled clinical trial following a completed pilot study. In four participating centres, 140 consenting patients with SSc and plantar foot pain will be randomised to receive either a commercially available pressure relieving and thermally insulating insole, or a sham insole with no cushioning or thermal properties. The primary end point is a reduction in pain measured using the Foot Function Index Pain subscale, 12 weeks after the start of intervention. Participants will complete the primary outcome measure (Foot Function Index pain sub-scale) prior to randomisation and at 12 weeks post randomisation. Secondary outcomes include participant reported pain and disability as derived from the Manchester Foot Pain and Disability Questionnaire and plantar pressures with and without the insoles in situ.
Discussion
This trial protocol proposes a rigorous and potentially significant evaluation of a simple and readily provided therapeutic approach which, if effective, could be of a great benefit for this group of patients.
Trial registration number
ISRCTN: ISRCTN02824122
doi:10.1186/1471-2474-13-11
PMCID: PMC3395828  PMID: 22309847
Foot pain; Plantar pressures; Scleroderma; Systemic sclerosis; Insoles
12.  Depression and anxiety in patients with rheumatoid arthritis: prevalence rates based on a comparison of the Depression, Anxiety and Stress Scale (DASS) and the hospital, Anxiety and Depression Scale (HADS) 
BMC Psychiatry  2012;12:6.
Background
While it is recognised that depression is prevalent in Rheumatoid Arthritis (RA), recent studies have also highlighted significant levels of anxiety in RA patients. This study compared two commonly used scales, the Depression Anxiety and Stress Scale (DASS) and the Hospital Anxiety and Depression Scale (HADS), in relation to their measurement range and cut points to consider the relative prevalence of both constructs, and if prevalence rates may be due to scale-specific case definition.
Methods
Patients meeting the criteria for RA were recruited in Leeds, UK and Sydney, Australia and asked to complete a survey that included both scales. The data was analysed using the Rasch measurement model.
Results
A total of 169 RA patients were assessed, with a repeat subsample, resulting in 323 cases for analysis. Both scales met Rasch model expectations. Using the 'possible+probable' cut point from the HADS, 58.3% had neither anxiety nor depression; 13.5% had anxiety only; 6.4% depression only and 21.8% had both 'possible+probable' anxiety and depression. Cut points for depression were comparable across the two scales while a lower cut point for anxiety in the DASS was required to equate prevalence.
Conclusions
This study provides further support for high prevalence of depression and anxiety in RA. It also shows that while these two scales provide a good indication of possible depression and anxiety, the estimates of prevalence so derived could vary, particularly for anxiety. These findings are discussed in terms of comparisons across studies and selection of scales for clinical use.
doi:10.1186/1471-244X-12-6
PMCID: PMC3285517  PMID: 22269280
13.  FcγRIIIa Expression on Monocytes in Rheumatoid Arthritis: Role in Immune-Complex Stimulated TNF Production and Non-Response to Methotrexate Therapy 
PLoS ONE  2012;7(1):e28918.
Objective
The expression of FcγRIIIa/CD16 may render monocytes targets for activation by IgG-containing immune complexes (IC). We investigated whether FcγRIIIa/CD16 was upregulated in rheumatoid arthritis (RA), associated with TNF production in response to IC-stimulation, and if this predicted response to methotrexate therapy.
Methods
FcγRIIIa/CD16 expression on CD14low and CD14++ monocytes was measured by flow cytometry in healthy controls and RA patients (early and long-standing disease). Intracellular TNF-staining was carried out after in vitro LPS or heat-aggregated immunoglobulin (HAG) activation. FcγRIIIa/CD16 expression pre- and post-steroid/methotrexate treatment was examined.
Results
Increased FcγRIIIa/CD16 expression on CD14++ monocytes in long-standing RA patients compared to controls was demonstrated (p = 0.002) with intermediate levels in early-RA patients. HAG-induced TNF-production in RA patients was correlated with the percentage of CD14++ monocytes expressing FcγRIIIa/CD16 (p<0.001). The percentage of CD14++ monocytes expressing FcγRIIIa/CD16 at baseline in early DMARD-naïve RA patients was negatively correlated with DAS28-ESR improvement 14-weeks post-methotrexate therapy (p = 0.003) and was significantly increased in EULAR non-responders compared to moderate (p = 0.01) or good responders (p = 0.003). FcγRIIIa/CD16 expression was not correlated with age, presence of systemic inflammation or autoantibody titers.
Conclusion
Increased FcγRIIIa/CD16 expression on CD14++ monocytes in RA may result in a cell that has increased responsiveness to IC-stimulation. This monocyte subset may contribute to non-response to methotrexate therapy.
doi:10.1371/journal.pone.0028918
PMCID: PMC3250404  PMID: 22235253
16.  Retreatment with rituximab based on a treatment-to-target approach provides better disease control than treatment as needed in patients with rheumatoid arthritis: a retrospective pooled analysis 
Rheumatology (Oxford, England)  2011;50(12):2223-2232.
Objective. To assess the efficacy and safety profiles of two different rituximab retreatment regimens in patients with RA.
Methods. Four hundred and ninety-three RA patients with an inadequate response to MTX recruited into rituximab Phase II/III studies received further courses of open-label rituximab based on two approaches: (i) treatment to target (TT): patients assessed 24 weeks after each course and retreated if not in remission [DAS in 28 joints based on ESR (DAS-28-ESR) ≥ 2.6]; (ii) treatment as needed (PRN): patients retreated at the physician’s discretion ≥24 weeks following the first course and ≥16 weeks following further courses, if both swollen and tender joint counts were ≥8. All courses consisted of i.v. rituximab 2 × 1000 mg 2 weeks apart plus MTX. Observed data were analysed according to treatment strategy.
Results. Multiple courses of rituximab maintained or improved responses irrespective of regimen. TT provided tighter control of disease activity with significantly greater improvements in DAS-28-ESR and lower HAQ-disability index scores vs PRN. TT resulted in significantly more patients achieving major clinical response. PRN resulted in recurrence of disease symptoms between courses, with TT significantly reducing the incidence of RA flares. Despite more frequent retreatment with TT compared with PRN, the rates of serious adverse events and serious infections were comparable between regimens.
Conclusions. Retreatment with rituximab based on 24-week evaluations and to a target of DAS-28-ESR remission leads to improved efficacy and tighter control of disease activity compared with PRN without a compromised safety profile. TT may be the preferable rituximab treatment regimen for patients with RA.
doi:10.1093/rheumatology/ker253
PMCID: PMC3222846  PMID: 21926153
Methotrexate-inadequate responder; Treatment to target; Treatment as needed; Retreatment; Rituximab; Treatment strategy
17.  The 2010 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Rheumatoid Arthritis 
Arthritis and rheumatism  2010;62(9):2582-2591.
Objective
The American College of Rheumatology and the European League Against Rheumatism have developed new classification criteria for rheumatoid arthritis (RA). The aim of Phase 2 of the development process was to achieve expert consensus on the clinical and laboratory variables that should contribute to the final criteria set.
Methods
Twenty-four expert RA clinicians (12 from Europe and 12 from North America) participated in Phase 2. A consensus-based decision analysis approach was used to identify factors (and their relative weights) that influence the probability of “developing RA,” complemented by data from the Phase 1 study. Patient case scenarios were used to identify and reach consensus on factors important in determining the probability of RA development. Decision analytic software was used to derive the relative weights for each of the factors and their categories, using choice-based conjoint analysis.
Results
The expert panel agreed that the new classification criteria should be applied to individuals with undifferentiated inflammatory arthritis in whom at least 1 joint is deemed by an expert assessor to be swollen, indicating definite synovitis. In this clinical setting, they identified 4 additional criteria as being important: number of joints involved and site of involvement, serologic abnormality, acute-phase response, and duration of symptoms in the involved joints. These criteria were consistent with those identified in the Phase 1 data-driven approach.
Conclusion
The consensus-based, decision analysis approach used in Phase 2 complemented the Phase 1 efforts. The 4 criteria and their relative weights form the basis of the final criteria set.
doi:10.1002/art.27580
PMCID: PMC3077961  PMID: 20872596
18.  A randomised, controlled study of outcome and cost effectiveness for RA patients attending nurse-led rheumatology clinics: Study protocol of an ongoing nationwide multi-centre study 
Background
The rise in the number of patients with arthritis coupled with understaffing of medical services has seen the deployment of Clinical Nurse Specialists in running nurse-led clinics alongside the rheumatologist clinics. There are no systematic reviews of nurse-led care effectiveness in rheumatoid arthritis. Few published RCTs exist and they have shown positive results for nurse-led care but they have several limitations and there has been no economic assessment of rheumatology nurse-led care in the UK.
Objective
This paper outlines the study protocol and methodology currently being used to evaluate the outcomes and cost effectiveness for patients attending rheumatology nurse-led clinics.
Design and methods
A multi-centred, pragmatic randomised controlled trial with a non-inferiority design; the null hypothesis being that of ‘inferiority’ of nurse-led clinics compared to physician-led clinics. The primary outcome is rheumatoid arthritis disease activity (measured by DAS28 score) and secondary outcomes are quality of life, self-efficacy, disability, psychological well-being, satisfaction, pain, fatigue and stiffness. Cost effectiveness will be measured using the EQ-5D, DAS28 and cost profile for each centre.
Power calculations
In this trial, a DAS28 change of 0.6 is considered to be the threshold for clinical distinction of ‘inferiority’. A sample size of 180 participants (90 per treatment arm) is needed to reject the null hypothesis of ‘inferiority’, given 90% power. Primary analysis will focus on 2-sided 95% confidence interval evaluation of between-group differences in DAS28 change scores averaged over 4 equidistant follow up time points (13, 26, 39 and 52 weeks). Cost effectiveness will be evaluated assessing the joint parameterisation of costs and effects.
Results
The study started in July 2007 and the results are expected after July 2011.
Trial registration
The International Standard Randomised Controlled Trial Number ISRCTN29803766.
doi:10.1016/j.ijnurstu.2011.01.010
PMCID: PMC3629570  PMID: 21334623
Nurse-led care; Clinical nurse specialists; Rheumatoid arthritis; Randomised controlled trial; Economic evaluation; Protocol
19.  Genetic variants at CD28, PRDM1, and CD2/CD58 are associated with rheumatoid arthritis risk 
Nature genetics  2009;41(12):1313-1318.
To discover novel RA risk loci, we systematically examined 370 SNPs from 179 independent loci with p<0.001 in a published meta-analysis of RA GWAS of 3,393 cases and 12,462 controls1. We used GRAIL2, a computational method that applies statistical text mining to PubMed abstracts, to score these 179 loci for functional relationships to genes in 16 established RA disease loci1,3-11. We identified 22 loci with a significant degree of functional connectivity. We genotyped 22 representative SNPs in an independent set of 7,957 cases and 11,958 matched controls. Three validate convincingly: CD2/CD58 (rs11586238, p=1×10−6 replication, p=1×10−9 overall), and CD28 (rs1980422, p=5×10−6 replication, p=1×10−9 overall), PRDM1 (rs548234, p=1×10−5 replication, p=2×10−8 overall). An additional four replicate (p<0.0023): TAGAP (rs394581, p=0.0002 replication, p=4×10−7 overall), PTPRC (rs10919563, p=0.0003 replication, p=7×10−7 overall), TRAF6/RAG1 (rs540386, p=0.0008 replication, p=4×10−6 overall), and FCGR2A (rs12746613, p=0.0022 replication, p=2×10−5 overall). Many of these loci are also associated to other immunologic diseases.
doi:10.1038/ng.479
PMCID: PMC3142887  PMID: 19898481
20.  Infliximab: 12 years of experience 
Arthritis Research & Therapy  2011;13(Suppl 1):S2.
Rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) are immune-mediated conditions that share an inflammatory mechanism fuelled by excessive cytokines, particularly TNF. Control of inflammation and rapid suppression of cytokines are important in treating these diseases. With this understanding and the corresponding advent of TNF inhibitors, RA patients, AS patients and PsA patients have found more choices than ever before and have greater hope of sustained relief. As a widely used TNF inhibitor, infliximab has a deep and established record of efficacy and safety data. Extensive evidence - from randomised controlled clinical trials, large registries and postmarketing surveillance studies - shows that infliximab effectively treats the signs and symptoms, provides rapid and prolonged suppression of inflammation, prevents radiologically observable disease progression and offers an acceptable safety profile in RA, AS and PsA. In very recent studies, investigators have observed drug-free remission in some patients. Additionally, infliximab may interfere with rapidly progressing disease in RA by early addition to methotrexate in patients with signs of an aggressive course. Finally, infliximab has been shown to reduce PsA clinical manifestations such as nail involvement. With our current understanding, substantial data and increasing confidence regarding use in practice, infliximab can be considered a well-known drug in our continued campaign against inflammatory rheumatic diseases.
doi:10.1186/1478-6354-13-S1-S2
PMCID: PMC3123963  PMID: 21624181
21.  Updated consensus statement on the use of rituximab in patients with rheumatoid arthritis 
Annals of the Rheumatic Diseases  2011;70(6):909-920.
Background
Since initial approval for the treatment of rheumatoid arthritis (RA), rituximab has been evaluated in clinical trials involving various populations with RA. Information has also been gathered from registries. This report therefore updates the 2007 consensus document on the use of rituximab in the treatment of RA.
Methods
Preparation of this new document involved many international experts experienced in the treatment of RA. Following a meeting to agree upon the core agenda, a systematic literature review was undertaken to identify all relevant data. Data were then interrogated by a drafting committee, with subsequent review and discussion by a wider expert committee leading to the formulation of an updated consensus statement. These committees also included patients with RA.
Results
The new statement covers wide-ranging issues including the use of rituximab in earlier RA and impact on structural progression, and aspects particularly pertinent to rituximab such as co-medication, optimal dosage regimens, repeat treatment cycles and how to manage non-response. Biological therapy following rituximab usage is also addressed, and safety concerns including appropriate screening for hepatitis, immunoglobulin levels and infection risk. This consensus statement will support clinicians and inform patients when using B-cell depletion in the management of RA, providing up-to-date information and highlighting areas for further research.
Conclusion
New therapeutic strategies and treatment options for RA, a chronic destructive and disabling disease, have expanded over recent years. These have been summarised in general strategic suggestions and specific management recommendations, emphasising the importance of expedient disease-modifying antirheumatic drug implementation and tight disease control. This consensus statement is in line with these fundamental principles of management.
doi:10.1136/ard.2010.144998
PMCID: PMC3086093  PMID: 21378402
24.  A modification of the Omeract RA MRI score for erosions for use with an extremity MRI system with reduced field of view 
Annals of the Rheumatic Diseases  2007;66(12):1669-1671.
Objectives
To develop and test the reliability of a modified version of the OMERACT rheumatoid arthritis magnetic resonance imaging score (RAMRIS) for erosions using extremity MRI (eMRI) with reduced field of view (RAMRIS‐RV).
Methods
Using a MagneVu 0.2 T machine, the preliminary RAMRIS‐RV assessed erosions in metacarpophalangeal (MCP) joints 2–3, bases of metacarpal (MC) 2–5, and all wrist bones excluding base MC 1, pisiform and trapezium. T1 weighted images of ⩾500 MCP and wrist bony sites from a mixed severity RA and control cohort were evaluated. An inter‐reader reliability study evaluating 300 wrist and 160 MCP bony sites was then performed.
Results
Mean per cent exact (and close) agreement results were as follows: MCP proximal sites 83.5 (96.2), MCP distal 54.4 (77.2), bases MC 2–4 85.2 (96.7), carpal bones 79.0 (92.1), distal radius/ulna 66.4 (87.8). The base of MCP 5 was visualised in ⩽50% cases (13/25) and was removed from the final RAMRIS‐RV.
Conclusions
The RAMRIS‐RV is a practical tool that can be used with eMRI with a reduced field of view. This study shows excellent inter‐reader reliability for erosion assessment, albeit in a reduced number of bony sites.
doi:10.1136/ard.2007.072561
PMCID: PMC2095331  PMID: 17616555
25.  Hand bone densitometry: a more sensitive standard for the assessment of early bone damage in rheumatoid arthritis 
Annals of the Rheumatic Diseases  2007;66(11):1513-1517.
Objective
To examine the role of hand dual‐energy x ray absorptiometry (DEXA) compared with radiography in the assessment of bone involvement in patients with early rheumatoid arthritis (RA) who have active disease.
Methods
The study population (n = 79) had RA of <12 months' duration and were selected for poor prognostic features. Clinical data and bone mineral density (BMD) data were collected at baseline, 24 and 48 weeks. Hand radiographs were performed at baseline and 48 weeks. Bone damage analyses were performed for the group and individuals using the smallest detectable change (SDC) method.
Results
At baseline, mean disease duration was 8.5 months, erythrocyte sedimentation rate was 34.3 mm/hour, C‐reactive protein was 40.2 mg/l, Health Assessment Questionnaire score was 1.35 and 81% of patients were positive for rheumatoid factor. Mean (95% CI) hand BMD loss was 2.5% (−3.5 to −1.5) at 24 weeks and 2.6% (−3.8 to −1.5) at 48 weeks. Individual hand bone loss exceeding the SDC was seen in 46.8% at 24 weeks and in 58.2% at 48 weeks. In the subgroup of 58 patients who had undergone radiography, radiographic joint damage score evaluated by the Sharp–van der Heijde method increased from 4.8 to 10.6 (p = 0.001). Individual hand bone loss in this subgroup exceeding the SDC was seen in 50.0% at 24 weeks and in 56.9% at 48 weeks, whereas at 48 weeks only 22.4% had deteriorated in modified Sharp score.
Conclusion
The study results indicate that hand DEXA is a more sensitive tool than radiology (radiographic joint‐damage scores), for measuring disease‐related bone damage in early RA.
doi:10.1136/ard.2006.067652
PMCID: PMC2111631  PMID: 17491097
early rheumatoid arthritis; bone densitometry; smallest detectable change

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